Synthetic genome recoding: new genetic codes for new features.

Full genome recoding, or rewriting codon meaning, through chemical synthesis of entire bacterial chromosomes has become feasible in the past several years. Recoding an organism can impart new properties including non-natural amino acid incorporation, virus resistance, and biocontainment. The estimated cost of construction that includes DNA synthesis, assembly by recombination, and troubleshooting, is now comparable to costs of early stage development of drugs or other high-tech products. Here, we discuss several recently published assembly methods and provide some thoughts on the future, including how synthetic efforts might benefit from the analysis of natural recoding processes and organisms that use alternative genetic codes

Dissecting the sharp response of a canonical developmental enhancer reveals multiple sources of cooperativity.

Developmental enhancers integrate graded concentrations of transcription factors (TFs) to create sharp gene expression boundaries. Here we examine the hunchback P2 (HbP2) enhancer which drives a sharp expression pattern in the Drosophila blastoderm embryo in response to the transcriptional activator Bicoid (Bcd). We systematically interrogate cis and trans factors that influence the shape and position of expression driven by HbP2, and find that the prevailing model, based on pairwise cooperative binding of Bcd to HbP2 is not adequate. We demonstrate that other proteins, such as pioneer factors, Mediator and histone modifiers influence the shape and position of the HbP2 expression pattern. Comparing our results to theory reveals how higher-order cooperativity and energy expenditure impact boundary location and sharpness. Our results emphasize that the bacterial view of transcription regulation, where pairwise interactions between regulatory proteins dominate, must be reexamined in animals, where multiple molecular mechanisms collaborate to shape the gene regulatory function

A Search for Overlapping Heritable Mechanisms Between Autism and Normal-range Personality Traits

Most cases of autism are thought to be primarily caused by the cumulative action of common low-effect variants. In this thesis, we explore the idea that these common variants serve an alternate function in the general population in helping create normal-range diversity of personality traits. We test our hypotheses in the Simons Simplex Collection, a repository of genomic and phenotypic data for over 2,500 families with autism. In particular, we analyze the relationship between autism in the children and personality traits in the parents, including the Broad Autism Phenotype (BAP) traits and technical subject matter interest. We show that the BAP traits have some SNP-based heritability, we find enrichment of autism genes in areas of the genome associated with the BAP traits through a genome-wide association study, and we observe greater inheritance of possible autism-risk genes by autistic offspring from parents with more intense BAP traits. We overcome moderate problems with statistical power by analyzing the effects of SNP aggregates rather than trying to find individually significant associations. Together, these results build a promising framework for a shared genetic basis between autism and autism-related personality traits that can be validated in the future with larger samples

Dissecting the sharp response of a canonical developmental enhancer reveals multiple sources of cooperativity.

Developmental enhancers integrate graded concentrations of transcription factors (TFs) to create sharp gene expression boundaries. Here we examine the hunchback P2 (HbP2) enhancer which drives a sharp expression pattern in the Drosophila blastoderm embryo in response to the transcriptional activator Bicoid (Bcd). We systematically interrogate cis and trans factors that influence the shape and position of expression driven by HbP2, and find that the prevailing model, based on pairwise cooperative binding of Bcd to HbP2 is not adequate. We demonstrate that other proteins, such as pioneer factors, Mediator and histone modifiers influence the shape and position of the HbP2 expression pattern. Comparing our results to theory reveals how higher-order cooperativity and energy expenditure impact boundary location and sharpness. Our results emphasize that the bacterial view of transcription regulation, where pairwise interactions between regulatory proteins dominate, must be reexamined in animals, where multiple molecular mechanisms collaborate to shape the gene regulatory function